The rising incidence of skin disorders, including non-melanoma disorders, as well as melanoma skin cancer, has been well documented, as has the continued lack of effective treatments of premalignant and malignant stages of skin cancer.
Diegpen, et al., Br. J. Dermatology 146: 1–6 (2002), have documented non-melanoma skin cancer, or “NMSC,” as the most common type of cancer affecting Caucasian populations. Approximately 80% of NMSCs are basal cell carcinomas, and 20% are squamous cell carcinomas. The condition known as actinic keratosis is a precancerous condition, which may develop into squamous cell carcinoma. The rate of progression to the invasive, squamous cell carcinoma, is estimated to range to up to 20% per year. See May, J. Am. Acad. Dermatol. 42: 8–10 (2000).
While melanoma represents only about 5% of all skin cancers in the U.S., it accounts for nearly 80% of skin cancer deaths. Early diagnosis leads to a high rate of cure by surgical excision; however, malignant melanoma has a very high tendency for invasion and to metastasize. Melanoma cells are highly resistant toward chemotherapy, all forms of therapeutic induction of apoptosis, as well as to any form of therapy.
It has recently been observed that cellular carbonyl stress, mediated by endogenous, reactive carbonyl species, or “RCS,” especially dicarbonyl compounds, including glyoxal, methylglyoxal, and malondialdelhyde, which are formed during glycolysis and lipid peroxidation, are implicated in both proliferative signaling, and metastasis of human tumor cells. See, e.g., Taguchi, et al., Nature 405(6784):354–60 (2000).
RCS—derived protein epitopes, referred to as “advanced glycation end products,” or “AGEs,” which are formed via reaction between RCS and tissue proteins, are found in abundance in melanoma, and AGEs are potent ligands of RAGE, which is a membrane receptor involved in melanoma proliferation and metastasis. See, e.g., Abe et al., J. Invest. Dermatol. 122(2), 461–467 (2004).
There is accumulating evidence to support the view that RCS which originate constitutively from increased tumor cells glycolysis, and mitochondrial lipid peroxidation, are small molecular anti-apoptotic modulators which suppress mitochondrial permeability transition pore opening, via covalent modifications. See, e.g., Speer, et al., J. Biol. Chem. 278(37), 34757–63.
Wondrak, et al., Biochem. Pharmacol. 7105: 1–13 (2002), have identified a series of very effective, non-toxic carbonyl scavengers, as being useful in therapeutic intervention of cellular carbonyl stress. This reference is incorporated by reference, as are U.S. Pat. No. 6,716,635, issued Apr. 6, 2004 and U.S. Pat. No. 6,417,235, issued Jul. 9, 2002. The '635 patent in particular gives a detailed explanation of RCS and RAGE compounds, mechanisms of action, how they are formed, and so forth.
It has now been found that these carbonyl scavengers have pronounced, apoptosis inducing impact on melanoma and other cancer cells, but not normal cells. This is a feature of the invention, as is set out in the examples which follow.